Arylsulfonylamino hydroxamic acid derivatives

ABSTRACT

A compound of formula (I), wherein n, X, R 3 , R 4  and Ar are as defined above, useful in the treatment of a condition selected from the group consisting of arthritis, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, scleritis and other diseases characterized by matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases involving the production of TNF. ##STR1##

This application is a 371 of PCT/US96/02679 filed Mar. 7, 1996 whichclaims priority from U.S. Ser. No. 08/401,049 filed Mar. 8, 1995 nowabandoned.

This application is a 371 of PCT/US96/02679 filed Mar. 7, 1996 whichclaims priority from U.S. Ser. No. 08/401,049 filed Mar. 8, 1995 nowabandoned.

BACKGROUND OF THE INVENTION

The present invention relates to arylsulfonylamino hydroxamic acidderivatives which are inhibitors of matrix metalloproteinases or theproduction of tumor necrosis factor (hereinafter also referred to asTNF) and as such are useful in the treatment of a condition selectedfrom the group consisting of arthritis, cancer, tissue ulceration,restenosis, periodontal disease, epidermolysis bullosa, scleritis andother diseases characterized by matrix metalloproteinase activity, AIDS,sepsis, septic shock and other diseases involving the production of TNF.

This invention also relates to a method of using such compounds in thetreatment of the above diseases in mammals, especially humans, and tothe pharmaceutical compositions useful therefor.

There are a number of enzymes which effect the breakdown of structuralproteins and which are structurally related metalloproteases.Matrix-degrading metalloproteinases, such as gelatinase, stromelysin andcollagenase, are involved in tissue matrix degradation (e.g. collagencollapse) and have been implicated in many pathological conditionsinvolving abnormal connective tissue and basement membrane matrixmetabolism, such as arthritis (e.g. osteoarthritis and rheumatoidarthritis), tissue ulceration (e.g. corneal, epidermal and gastriculceration), abnormal wound healing, periodontal disease, bone disease(e.g. Paget's disease and osteoporosis), tumor metastasis or invasion,as well as HIV-infection (J. Leuk. Biol., 52 (2):244-248, 1992).

Tumor necrosis factor is recognized to be involved in many infectiousand auto-immune diseases (W. Friers, FEBS Letters, 1991, 285, 199).Furthermore, it has been shown that TNF is the prime mediator of theinflammatory response seen in sepsis and septic shock (C. E. Spooner etal., Clinical Immunology and Immunopathology, 1992, 62 S11).

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula ##STR2## orthe pharmaceutically acceptable salts thereof, wherein n is 1 to 6;

X is hydroxy, (C₁ -C₆)alkoxy or NR¹ R² wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, piperidyl, (C₁ -C₆)alkylpiperidyl, (C₆ -C₁₀)arylpiperidyl,(C₅ -C₉)heteroarylpiperidyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkylpiperidyl, (C₅-C₉)heteroaryl(C₁ -C₆)alkylpiperidyl, (C₁ -C₆)acylpiperidyl, (C₆-C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₅-C₉)heteroaryl(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl, (C₆-C₁₀)aryl(C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁ -C₆)alkyl, R⁵ (C₂ -C₆)alkyl, (C₁ -C₅)alkyl(CHR⁵) (C₁-C₆)alkyl wherein R⁵ is hydroxy, (C₁ -C₆)acyloxy, (C₁ -C₆)alkoxy,piperazino, (C₁ -C₆)alkylamino, (C₁ -C₆)alkylthio, (C₆ -C₁₀)arylthio,(C₁ -C₆)alkylsulfinyl, (C₆ -C₁₀)arylsulfinyl, (C₁ -C₆)alkylsulfoxyl, (C₆-C₁₀)arylsulfoxyl, amino, (C₁ -C₆)alkylamino, ((C₁ -C₆)alkyl)₂ amino,(C₁ -C₆)acylpiperazino, (C₁ -C₆)alkylpiperazino, (C₆ -C₁₀)aryl(C₁-C₆)alkylpiperazino, (C₅ -C₉)heteroaryl(C₁ -C₆)alkylpiperazino,morpholino, thiomorpholino, piperidino or pyrrolidino; R⁶ (C₁ -C₆)alkyl,(C₁ -C₅)alkyl(CHR⁶)(C₁ -C₆)alkyl wherein R⁶ is piperidyl, (C₁-C₆)alkylpiperidyl, (C₆ -C₁₀)arylpiperidyl, (C₆ -C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅ -C₉)heteroarylpiperidyl or (C₅ -C₉)heteroaryl(C₁-C₆)alkylpiperidyl; and CH(R⁷)COR⁸ wherein R⁷ is hydrogen, (C₁-C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl,(C₁ -C₆)alkylthio(C₁ -C₆)alkyl, (C₆ -C₁₀)arylthio(C₁ -C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁-C₆)alkylsulfonyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfonyl(C₁ -C₆)alkyl,hydroxy(C₁ -C₆)alkyl, amino(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino(C₁-C₆)alkyl, ((C₁ -C₆)alkylamino)₂ (C₁ -C₆)alkyl, R⁹ R¹⁰ NCO(C₁ -C₆)alkylor R⁹ OCO(C₁ -C₆)alkyl wherein R⁹ and R¹⁰ are each independentlyselected from the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₆-C₁₀)aryl(C₁ -C₆)alkyl and (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl; and R⁸ isR¹¹ O or R¹¹ R¹² N wherein R¹¹ and R¹² are each independently selectedfrom the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁-C₆)alkyl and (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl;

or R¹ and R², or R⁹ and R¹⁰, or R¹¹ and R¹² may be taken together toform an azetidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,(C₁ -C₆)acylpiperazinyl, (C₁ -C₆)alkylpiperazinyl, (C₆-C₁₀)arylpiperazinyl, (C₅ -C₉)heteroarylpiperazinyl or a bridgeddiazabicycloalkyl ring selected from the group consisting of ##STR3##wherein r is 1, 2 or 3; m is 1 or 2;

p is 0 or 1; and

Q is hydrogen, (C_(l) -C₃)alkyl or (C₁ -C₆)acyl;

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁ -C₆)alkyl,(C₁ -C₆)alkyl (difluoromethylene), (C₁ -C₃)alkyl(difluoromethylene) (C₁-C₃)alkyl, (C₆ -C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₆ -C₁₀)aryl(C_(l)-C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl,(C₆ -C₁₀)aryl(C₁ -C₁₀)aryl(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁ -C₆)alkyl, hydroxy(C₁ -C₆)alkyl, (C₁ -C₆)acyloxy(C₁-C₆)alkyl, (C₁ -C₆)alkoxy(C₁ -C₆)alkyl, piperazinyl(C₁ -C₆)alkyl, (C₁-C₆)acylamino(C₁ -C₆)alkyl, piperidyl, (C₁ -C₆)alkylpiperidyl, (C₆-C₁₀)aryl(C₁ -C₆)alkoxy(C₁ -C₆)alkyl, (C₅ -C₉)heteroaryl(C₁-C₆)alkoxy(C₁ -C₆)alkyl, (C₁ -C₆)alkylthio(C₁ -C₆)alkyl, (C₆-C₁₀)arylthio(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfinyl(C₁ -C₆)alkyl, (C₆-C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfonyl(C₁ -C₆)alkyl, (C₆-C₁₀)arylsulfonyl(C₁ -C₆)alkyl, amino(C₁ -C₆)alkyl, (C₁-C₆)alkylamino(C₁ -C₆)alkyl, ((C₁ -C₆)alkylamino)₂ (C₁ -C₆)alkyl, R¹³CO(C₁ -C₆)alkyl wherein R¹³ is R²⁰ O or R²⁰ R²¹ N wherein R²⁰ and R²¹are each independently selected from the group consisting of hydrogen,(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl or (C₅ -C₉)heteroaryl(C₁-C₆)alkyl; or R¹⁴ (C₁ -C₆)alkyl wherein R¹⁴ is (C₁ -C₆)acylpiperazino,(C₆ -C₁₀)arylpiperazino, (C₅ -C₉)heteroarylpiperazino, (C₁-C₆)alkylpiperazino, (C₆ -C₁₀)aryl(C₁ -C₆)alkylpiperazino, (C₅-C₉)heteroaryl(C₁ -C₆)alkylpiperazino, morpholino, thiomorpholino,piperidino, pyrrolidino, piperidyl, (C₁ -C₆)alkylpiperidyl, (C₆-C₁₀)arylpiperidyl, (C₅ -C₉)heteroarylpiperidyl, (C₆ -C₁₀)aryl(C₁-C₆)alkylpiperidyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkylpiperidyl or (C₁-C₆)acylpiperidyl;

or R³ and R⁴, or R²⁰ and R²¹ may be taken together to form a (C₃-C₆)cycloalkyl, oxacyclohexyl, thiocyclohexyl, indanyl or tetralinylring or a group of the formula ##STR4## wherein R¹⁵ is hydrogen, (C₁-C₆)acyl, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₅-C₉)heteroaryl(C₁ -C₆)alkyl or (C₁ -C₆)alkylsulfonyl; and

Ar is (C₆ -C₁₀)aryl, (C₅ -C₉)heteroaryl, (C₁ -C₆)alkyl(C₆ -C₁₀)aryl, (C₁-C₆)alkoxy(C₆ -C₁₀)aryl, ((C₁ -C₆)alkoxy)₂ (C₆ -C₁₀)aryl, (C₆-C₁₀)aryloxy(C₆ -C₁₀)aryl, (C₅ -C₉)heteroaryloxy(C₆ -C₁₀)aryl, (C₁-C₆)alkyl(C₅ -C₉)heteroaryl, (C₁ -C₆)alkoxy(C₅ -C₉)heteroaryl, ((C₁-C₆)alkoxy)₂ (C₅ -C₉)heteroaryl, (C₆ -C₁₀)aryloxy(C₅ -C₉)heteroaryl, (C₅-C₉)heteroaryloxy(C₅ -C₉)heteroaryl;

with the proviso that when either R¹ or R² is CH(R⁷)COR⁸ wherein R⁷ andR⁸ are as defined above, the other of R¹ or R² is hydrogen, (C₁-C₆)alkyl or benzyl.

The term "alkyl", as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof.

The term "alkoxy", as used herein, includes O-alkyl groups wherein"alkyl" is defined above.

The term "aryl", as used herein, unless otherwise indicated, includes anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3substituents selected from the group consisting of fluoro, chloro,trifluoromethyl, (C₁ -C₆)alkoxy, (C₆ -C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy and (C₁ -C₆)alkyl.

The term "heteroaryl", as used herein, unless otherwise indicated,includes an organic radical derived from an aromatic heterocycliccompound by removal of one hydrogen, such as pyridyl, furyl, pyroyl,thienyl, isothiazolyl, imidazolyl, benzimidazolyl, terazolyl, pyrazinyl,pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl,benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl,isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl,optionally substituted by 1 to 2 substituents selected from the groupconsisting of fluoro, chloro, trifluoromethyl, (C₁ -C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy and (C₁ -C₆)alkyl.

The term "acyl", as used herein, unless otherwise indicated, includes aradical of the general formula RCO wherein R is alkyl, alkoxy, aryl,arylalkyl or aryalkyloxy and the terms "alkyl" or "aryl" are as definedabove.

The term "acyloxy", as used herein, includes O-acyl groups wherein"acyl" is defined above.

The compound of formula I may have chiral centers and therefore exist indifferent enantiomeric forms. This invention relates to all opticalisomers and stereoisomers of the compounds of formula I and mixturesthereof.

Preferred compounds of formula I include those wherein n is 2.

Other preferred compounds of formula I include those wherein Ar is4-methoxyphenyl or 4-phenoxyphenyl.

Other preferred compounds of formula I include those wherein either R³or R⁴ is not hydrogen.

Other preferred compounds of formula I include those wherein n is 1 andeither R¹ or R² is hydrogen.

Other preferred compounds of formula I include those wherein X ishydroxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl and either R³ or R⁴ isnot hydrogen.

Other preferred compounds of formula I include those wherein X isalkoxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl and either R³ or R⁴ isnot hydrogen.

Other preferred compounds of formula I include those wherein Ar is4-methoxyphenyl or 4-phenoxyphenyl and R³ and R⁴ are taken together toform (C₃ -C₆)cycloalkanyl, oxacyclohexanyl, thiocyclohexanyl, indanyl ora group of the formula ##STR5## wherein R¹⁵ is (C₁ -C₆)acyl, (C₁-C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₅ -C₉)heteroaryl(C₁ -C₆)alkylor (C₁ -C₆)alkylsulfonyl.

More preferred compounds of formula I are those wherein n is 2, Ar is4-methoxyphenyl or 4-phenoxyphenyl, R¹ and R² are taken together to formpiperazinyl, (C₁ -C₆)alkylpiperazinyl, (C₆ -C₁₀)aryl piperazinyl or (C₅-C₉)heteroaryl(C₁ -C₆)alkylpiperazinyl, and either R³ or R⁴ is nothydrogen or both R³ and R⁴ are not hydrogen.

More preferred compounds of formula I are those wherein n is 2, Ar is4-methoxyphenyl or 4-phenoxyphenyl, R¹ is hydrogen or (C₁ -C₆)alkyl, R²is 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R³ orR⁴ is not hydrogen or both R³ and R⁴ are not hydrogen.

More preferred compounds of formula I are those wherein n is 1, Ar is4-methoxyphenyl or 4-phenoxyphenyl, R¹ is hydrogen, R² is2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl, and either R³ or R⁴is not hydrogen or both R³ and R⁴ are not hydrogen.

More preferred compounds of formula I are those wherein n is 2, Ar is4-methoxyphenyl, R¹ is hydrogen or (C₁ -C₆)alkyl and R² is R⁵ (C₂-C₆)alkyl wherein R⁵ is morpholino, thiomorpholino, piperidino,pyrrolidino, (C₁ -C₆)acylpiperazino, (C₁ -C₆)alkylpiperazino, (C₆-C₁₀)arylpiperazino, (C₅ -C₉)heteroarylpiperazino, (C₆ -C₁₀)aryl(C₁-C₆)alkylpiperazino or (C₅ -C₉)heteroaryl(C₁ -C₆)alkylpiperazino andeither R³ or R⁴ is not hydrogen or both R³ and R⁴ are not hydrogen.

More preferred compounds of formula I are those wherein n is 1, Ar is4-methoxyphenyl or 4-phenoxyphenyl, R¹ is hydrogen, R² is R⁵ (C₂-C₆)alkyl wherein R⁵ is morpholino, thiomorpholino, piperidino,pyrrolidino (C₁ -C₆)acylpiperazino, (C₁ -C₆)alkylpiperazino, (C₆-C₁₀)arylpiperazino, (C₅ -C₉)heteroarylpiperazino, (C₆ -C₁₀)aryl(C₁-C₆)alkylpiperazino or (C₅ -C₉)heteroaryl(C₁ -C₆)alkylpiperazino andeither R³ or R⁴ is not hydrogen or both R³ and R⁴ are not hydrogen.

Specific preferred compounds of formula I include the following:

2-(R)-N-Hydroxy-2-(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methylbutyramide;

2-(R)-2-(2-Benzylcarbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide;

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) (2-(pyridin-3-ylmethyl)-carbamoyl!ethyl)amino)-3-methylbutyramide;

2-(R)-N-Hydroxy-2-( 4-methoxybenzenesulfonyl!2-(methylpyridin-3-ylmethylcarbamoyl)ethyl!amino)-3-methylbutyramide;

4-(3-1-(R)-1-Hydroxycarbamoyl-2-methylpropyl)(4-methoxybenzenesulfonyl)amino!propionyl)piperazine-1-carboxylicacid, tert-butyl ester;

2-(R)-N-Hydroxy-2-(4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-1-ylpropyl)amino)-3-methylbutyramidehydrochloride;

2-(R)-2-(Benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!N-hydroxy-3-methylbutyramide;

2-(R) -N-Hydroxy-2-( 4-methoxybenzenesulfonyl!-(2-morpholin-4-ylethylcarbamoyl)methyl!amino)-3-methylbutyramide; and

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) ((pyridin-3-ylmethyl)carbamoyl!methyl)amino)-3-methylbutyramide.

Other specific compounds of formula I include the following:

2-(R)-3,3,3-Trifluoro-N-hydroxy-2- (methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!propionamide;

2-(R)-N-Hydroxy-2-((4-phenoxybenzenesulfonyl)2-(methylpyridin-4-ylmethylcarbamoyl)ether!amino)-3-methylbutyramide;

4-4-Methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-1-methylpiperidene-4-carboxylicacid hydroxyamide;

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-3-(4-methylpiperazin-1-yl)-3-oxopropyl!amino)-3-methylbutyramide;

2-(R)-2-(2-Carboxyethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide;

(2-Carboxyethyl)(3,4-dimethoxybenzenesulfonyl)amino!-N-hydroxy-acetamide;

2-(R)-2-(2-Carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide;

2-(R),3-(R)-3,N-Dihydroxy-2-(4-methoxybenzenesulfonyl)(3-oxo-3-piperidin-1-ylpropyl)amino!-butyramide;

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)3-(methylpyridin-3-ylmethylcarbamoyl)propyl!amino)-3-methylbutyramide;

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)2-(methylcarboxymethylcarbamoyl)ethyl!amino)-3-methylbutyramide;

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)-(1-methylpiperidin-4-ylcarbamoyl)methyl!amino)-3-methylbutyramide;

2-(R)-2-Cyclohexyl-N-hydroxy-2-((4-methoxybenzenesulfonyl)-3-(4-methylpiperazin-1-yl)-3-oxopropyl!amino)-acetamide;

2-(R)-N-Hydroxy-2-(methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-4-(morpholin-4-yl)butyramide.

The present invention also relates to a pharmaceutical composition for(a) the treatment of a condition selected from the group consisting ofarthritis, cancer, tissue ulceration, restenosis, periodontal disease,epidermolysis bullosa, scleritis and other diseases characterized bymatrix metalloproteinase activity, AIDS, sepsis, septic shock and otherdiseases involving the production of tumor necrosis factor (TNF) or (b)the inhibition of matrix metalloproteinases or the production of tumornecrosis factor (TNF) in a mammal, including a human, comprising anamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof, effective in such treatments and a pharmaceutically acceptablecarrier.

The present invention also relates to a method for the inhibition of (a)matrix metalloproteinases or (b) the production of tumor necrosis factor(TNF) in a mammal, including a human, comprising administering to saidmammal an effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof.

The present invention also relates to a method for treating a conditionselected from the group consisting of arthritis, cancer, tissueulceration, restenosis, periodontal disease, epidermolysis bullosa,scleritis and other diseases characterized by matrix metalloproteinaseactivity, AIDS, sepsis, septic shock and other diseases involving theproduction of tumor necrosis factor (TNF) in a mammal, including ahuman, comprising administering to said mammal an amount of a compoundof claim 1 or a pharmaceutically acceptable salt thereof, effective intreating such a condition.

DETAILED DESCRIPTION OF THE INVENTION

The following reaction Schemes illustrate the preparation of thecompounds of the present invention. Unless otherwise indicated R¹, R²,R³, R⁴, n and Ar in the reaction Schemes and the discussion that followare defined as above. ##STR6##

In reaction 1 of Scheme 1, the amino acid compound of formula VII,wherein R¹⁶ is (C₁ -C₆)alkyl, benzyl, allyl or tert-butyl, is convertedto the corresponding compound of formula VI by reacting VII with areactive functional derivative of an arylsulfonic acid compound, such asan arylsulfonyl chloride, in the presence of a base, such astriethylamine, and a polar solvent, such as tetrahydrofuran, dioxane,water or acetonitrile, preferably a mixture of dioxane and water. Thereaction mixture is stirred, at room temperature, for time periodbetween about 10 minutes to about 24 hours, preferably about 60 minutes.

In reaction 2 of Scheme 1, the arylsulfonyl amino compound of formulaVI, wherein R¹⁶ is (C₁ -C₆)alkyl, benzyl, allyl or tert-butyl, isconverted to the corresponding compound of formula V, wherein n is 1, 3,4, 5 or 6, by reacting VI with a reactive derivative of an alcohol ofthe formula ##STR7## such as the chloride, bromide or iodide derivative,preferably the bromide derivative, wherein the R¹⁷ protecting group is(C₁ -C₆)alkyl, benzyl, allyl or tert-butyl, in the presence of a basesuch as potassium carbonate or sodium hydride, preferably sodiumhydride, and a polar solvent, such as dimethylformamide. The reactionmixture is stirred, at room temperature, for a time period between about60 minutes to about 48 hours, preferably about 18 hours. The R¹⁷protecting group is chosen such that it may be selectively removed inthe presence of and without loss of the R¹⁶ protecting group, therefore,R¹⁷ cannot be the same as R¹⁶. Removal of the R¹⁷ protecting group fromthe compound of formula V to give the corresponding carboxylic acid offormula IV, in reaction 3 of Scheme 1, is carried out under conditionsappropriate for that particular R¹⁷ protecting group in use which willnot affect the R¹⁶ protecting group. Such conditions include; (a)saponification where R¹⁷ is (C₁ -C₆)alkyl and R¹⁶ is tert-butyl, (b)hydrogenolysis where R¹⁷ is benzyl and R¹⁶ is tert-butyl or (C₁-C₆)alkyl, (c) treatment with a strong acid such as trifluoroacetic acidor hydrochloric acid where R¹⁷ is tert-butyl and R¹⁶ is (C₁ -C₆)alkyl,benzyl or allyl, or (d) treatment with tributyltinhydride and aceticacid in the presence of catalytic bis(triphenylphosphine) palladium (II)chloride where R¹⁷ is allyl and R¹⁶ is (C₁ -C₆)alkyl, benzyl ortert-butyl.

In reaction 4 of Scheme 1, the carboxylic acid of formula IV iscondensed with an amine, R¹ R² NH, or the salt thereof, to give thecorresponding amide compound of formula III. The formation of amidesfrom primary or secondary amines or ammonia and carboxylic acids isachieved by conversion of the carboxylic acid to an activated functionalderivative which subsequently undergoes reaction with a primary orsecondary amine or ammonia to form the amide. The activated functionalderivative may be isolated prior to reaction with the primary orsecondary amine or ammonia. Alternatively, the carboxylic acid may betreated with oxalyl chloride or thionyl chloride, neat or in an inertsolvent, such as chloroform, at a temperature between about 25° C. toabout 80° C., preferably about 50° C., to give the corresponding acidchloride functional derivative. The inert solvent and any remainingoxalyl chloride or thionyl chloride is then removed by evaporation undervacuum. The remaining acid chloride functional derivative is thenreacted with the primary or secondary amine or ammonia in an inertsolvent, such as methylene chloride, to form the amide. The preferredmethod for the condensation of the carboxylic acid of formula IV with anamine to provide the corresponding amide compound of formula III is thetreatment of IV with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate in the presence of a base, such astriethylamine, to provide the benzotriazol-1-oxy ester in situ which, inturn, reacts with the amine, R¹ R² N, in an inert solvent, such asmethylene chloride, at room temperature to give the amide compound offormula III.

Removal of the R¹⁶ protecting group from the compound of formula III togive the corresponding carboxylic acid of formula II, in reaction 5 ofScheme 1, is carried out under conditions appropriate for the particularR¹⁶ protecting group in use. Such conditions include; (a) saponificationwhere R¹⁶ is lower alkyl, (b) hydrogenolysis where R¹⁶ is benzyl, (c)treatment with a strong acid, such as trifluoroacetic acid orhydrochloric acid, where R¹⁶ is tert-butyl, or (d) treatment withtributyltinhydride and acetic acid in the presence of catalyticbis(triphenylphosphine) palladium (II) chloride where R¹⁶ is allyl.

In reaction 6 of Scheme 1, the carboxylic acid compound of formula II isconverted to the hydroxamic acid compound of formula I by treating IIwith1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and1-hydroxybenztriazole in a polar solvent, such as dimethylformamide,followed by the addition of hydroxylamine to the reaction mixture aftera time period between about 15 minutes to about 1 hour, preferably about30 minutes. The hydroxylamine is preferably generated in situ from asalt form, such as hydroxylamine hydrochloride, in the presence of abase, such as N-methylmorpholine. Alternatively, a protected derivativeof hydroxylamine or its salt form, where the hydroxyl group is protectedas a tert-butyl, benzyl or allyl ether, may be used in the presence of(benzotriazol-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate and a base, such as N-methylmorpholine. Removal ofthe hydroxylamine protecting group is carried out by hydrogenolysis fora benzyl protecting group or treatment with a strong acid, such astrifluoroacetic acid, for a tert-butyl protecting group. The allylprotecting group may be removed by treatment with tributyltinhydride andacetic acid in the presence of catalytic bis(triphenylphosphine)palladium (II) chloride. N,O-bis(4-methoxybenzyl)hydroxylamine may alsobe used as the protected hydroxylamine derivative where deprotection isachieved using a mixture of methanesulfonic acid and trifluoroaceticacid.

In reaction 1 of Scheme 2, the arylsulfonylamino compound of formula VI,wherein R¹⁶ is (C₁ -C₆)alkyl, benzyl or tert-butyl, is converted to thecorresponding compound of formula VIII, wherein R¹⁸ is 2-propenyl or3-butenyl, by reacting IX with a reactive functional derivative, such asthe halide, preferably the iodide derivative, of 2-propen-1-ol when R¹⁸is 2-propenyl or 3-buten-1-ol when R¹⁸ is 3-butenyl, in the presence ofa base, such as potassium carbonate, cesium carbonate or sodium hydride,preferably sodium hydride when R¹⁸ is 2-propenyl or cesium carbonatewhen R¹⁸ is 3-butenyl. The reaction is stirred in a polar solvent, suchas dimethylformamide, at room temperature, for a time period betweenabout 2 hours to about 48 hours, preferably about 18 hours.

In reaction 2 of Scheme 2, the compound of formula VIII is converted tothe carboxylic acid compound of formula IV, wherein n is 2. The compoundof formula VIII, wherein R¹⁸ is 2-propenyl, is converted to the compoundof formula IV, wherein n is 2, by reacting VIII withborane-dimethylsulfide complex, followed by immediate oxidation usingchromium trioxide in aqueous acetic acid. The oxidative cleavage ofterminal olefins to carboxylic acids can be achieved by several methodsknown in the art. The preferred method for the oxidative cleavage of thecompound of formula VIII, wherein R¹⁸ is 3-butenyl, to obtain thecarboxylic acid compound of formula IV is to react VIII with sodiumperiodate in the presence of a catalytic amount of ruthenium (III)chloride in a mixture of carbon tetrachloride, acetonitrile and water.

The compound of formula IV, wherein n is 2, is further reacted toprovide the hydroxamic acid compound of formula I, wherein n is 2,according to the procedure described above in reactions 4, 5 and 6 ofScheme 1.

An alternative method for the synthesis of the hydroxamic acid compoundof formula I, wherein n is 1 and R³ and R⁴ are both hydrogen, is shownin reaction 1 of Scheme 3, beginning with reacting iminoacetic acid or ametal or ammonium salt of iminoacetic acid of formula X with afunctional derivative of an arylsulfonic acid compound, such as anarylsulfonyl chloride, at room temperature, in the presence of asuitable base, such as triethylamine, and a polar solvent such astetrahydrofuran, dioxane, water or acetonitrile, preferably a mixture ofdioxane and water, to give the corresponding dicarboxylic acid compoundof formula XI.

In reaction 2 of Scheme 3, the dicarboxylic acid compound of formula XIis dehydrated to give a cyclic anhydride compound of formula XII. Theformation of cyclic anhydrides by dehydration of dicarboxylic acids maybe achieved by a variety of means. The preferred method for thedehydration of the dicarboxylic acid compound of formula XI to give acyclic anhydride compound of formula XII is to treat XI with an excessof acetic anhydride at a temperature between about 25° C. to about 80°C., preferably about 60° C. Excess acetic anhydride and acetic acid, aby-product of the reaction, are removed by evaporation under reducedpressure leaving the cyclic anhydride compound of formula XII.

In reaction 3 of Scheme 3, the cyclic anhydride compound of formula XIIis reacted, at room temperature, with an amine, NR¹ R², or a salt of theamine, such as the hydrochloride, in the presence of a base, such astriethylamine, to give the carboxylic acid of formula II, wherein n is 1and R³ and R⁴ are both hydrogen. Suitable solvents for the reaction arethose that will not react with the starting materials, which includechloroform, methylene chloride and dimethylformamide, preferablymethylene chloride.

The compound of formula II is further reacted to give the hydroxamicacid compound of formula I, wherein n is 1 and R³ and R⁴ are bothhydrogen, according to the procedure described above in reaction 6 ofScheme 1.

In reaction 1 of Scheme 4, the carboxylic acid compound of formula IV,wherein n is 2, is converted to the corresponding compound of formula V,wherein R¹⁹ is (C₁ -C₆)alkyl or tert-butyl, by reacting IV with acompound of the formula

    (R.sup.19 O).sub.2 CHN(CH.sub.3).sub.2

wherein R¹⁹ is (C₁ -C₆)alkyl or tert-butyl, in an inert solvent, such astoluene, at a temperature between about 60° C. to about 100° C.,preferably about 100° C., for a time period between about 1 hour toabout 3 hours, preferably 2 hours. In reaction 2 of Scheme 4, thearylsulfonyl amino compound of formula VI wherein n is 1, 3, 4, 5 or 6and R¹⁶ is (C₁ -C₆)alkyl, benzyl, allyl or tert-butyl, is converted tothe corresponding compound of formula XIII, wherein R¹⁹ is (C₁ -C₆)alkylor tert-butyl, by reacting VI with a reactive derivative of an alcoholof the formula ##STR8## such as the chloride, bromide or iodidederivative, preferably the bromide derivative, wherein R¹⁹ is (C₁-C₆)alkyl or tert-butyl, in the presence of a base such as potassiumcarbonate or sodium hydride, preferably sodium hydride, and a polarsolvent, such as dimethylformamide. The reaction is stirred, at roomtemperature, for a time period between about 60 minutes to about 48hours, preferably about 18 hours. The R¹⁶ protecting group, of thecompounds of formulas IV and VI, is chosen such that it may beselectively removed in the presence of and without loss of the R¹⁹ (C₁-C₆)alkyl or tert-butyl group, therefore, R¹⁶ cannot be the same as R¹⁹.Removal of the R¹⁶ protecting group from the compound of formula XIII togive the corresponding carboxylic acid of formula XIV, wherein n is 1 to6, in reaction 3 of Scheme 4, is carried out under conditionsappropriate for that particular R¹⁶ protecting group in use which willnot affect the R¹⁹ (C₁ -C₆)alkyl or tert-butyl group. Such conditionsinclude; (a) saponification where R¹⁶ is (C₁ -C₆)alkyl and R¹⁹ istert-butyl, (b) hydrogenolysis where R¹⁶ is benzyl and R¹⁹ is tert-butylor (C₁ -C₆)alkyl, (c) treatment with a strong acid such astrifluoroacetic acid or hydrochloric acid where R¹⁶ is tert-butyl andR¹⁹ is (C₁ -C₆)alkyl, or (d) treatment with tributyltinhydride andacetic acid in the presence of catalytic bis(triphenylphosphine)palladium (II) chloride where R¹⁶ is allyl and R¹⁹ is (C₁ -C₆)alkyl ortert-butyl.

In reaction 4 of Scheme 4, the carboxylic acid of formula XIV isconverted to the hydroxamic acid compound of formula XV, wherein n is 1to 6, by treating XIV with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideand 1-hydroxybenztriazole in a polar solvent, such as dimethylformamide,followed by the addition of hydroxylamine to the reaction mixture aftera time period between about 15 minutes to about 1 hour, preferably about30 minutes. The hydroxylamine is preferably generated in situ from asalt form, such as hydroxylamine hydrochloride, in the presence of abase, such as N-methylmorpholine. Alternatively, a protected derivativeof hydroxylamine or its salt form, where the hydroxyl group is protectedas a tert-butyl, benzyl or allyl ether, may be used in the presence of(benzotriazol-1-yloxy)tris(dimethylamino) phosphoniumhexafluorophosphate and a base, such as N-methylmorpholine. Removal ofthe hydroxylamine protecting groups is carried out by hydrogenolysis fora benzyl protecting group or treatment with a strong acid, such astrifluoroacetic acid, for a tert-butyl protecting group. The allylprotecting group may be removed by treatment with tributyltinhydride andacetic acid in the presence of catalytic bis(triphenylphosphine)palladium (II) chloride. N,O-bis(4-methoxybenzyl)hydroxylamine may alsobe used, when R¹⁹ is (C₁ -C₆)alkyl, as the protected hydroxylaminederivative where deprotection is achieved using a mixture ofmethanesulfonic acid and trifluoroacetic acid.

In reaction 5 of Scheme 4, the amide formula of formula XV is, ifdesired, converted to the corresponding carboxylic acid compound offormula XVI by (a) saponification where R¹⁹ is lower alkyl or (b)treatment with a strong acid, such as trifluoroacetic acid orhydrochloric acid, where R¹⁹ is tert-butyl.

Pharmaceutically acceptable salts of the acidic compounds of theinvention are salts formed with bases, namely cationic salts such asalkali and alkaline earth metal salts, such as sodium, lithium,potassium, calcium, magnesium, as well as ammonium salts, such asammonium, trimethyl-ammonium, diethylammonium, andtris-(hydroxymethyl)-methylammonium salts.

Similarly acid addition salts, such as of mineral acids, organiccarboxylic and organic sulfonic acids e.g. hydrochloric acid,methanesulfonic acid, maleic acid, are also possible provided a basicgroup, such as pyridyl, constitutes part of the structure.

The ability of the compounds of formula I or their pharmaceuticallyacceptable salts (hereinafter also referred to as the compounds of thepresent invention) to inhibit matrix metalloproteinases or theproduction of tumor necrosis factor (TNF) and, consequently, demonstratetheir effectiveness for treating diseases characterized by matrixmetalloproteinase or the production of tumor necrosis factor is shown bythe following in vitro assay tests.

BIOLOGICAL ASSAY Inhibition of Human Collagenase (MMP-1)

Human recombinant collagenase is activated with trypsin using thefollowing ratio: 10 μg trypsin per 100 μg of collagenase. The trypsinand collagenase are incubated at room temperature for 10 minutes then afive fold excess (50 μg/10 μg trypsin) of soybean trypsin inhibitor isadded.

10 mM stock solutions of inhibitors are made up in dimethyl sulfoxideand then diluted using the following Scheme:

10 mM→120 μM→12 μM→1.2 μM→0.12 μM

Twenty-five microliters of each concentration is then added intriplicate to appropriate wells of a 96 well microfluor plate. The finalconcentration of inhibitor will be a 1:4 dilution after addition ofenzyme and substrate. Positive controls (enzyme, no inhibitor) are setup in wells D1-D6 and blanks (no enzyme, no inhibitors) are set in wellsD7-D12.

Collagenase is diluted to 400 μg/ml and 25 μl is then added toappropriate wells of the microfluor plate. Final concentration ofcollagenase in the assay is 100 ng/ml.

Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂) is made as a 5mM stock in dimethyl sulfoxide and then diluted to 20 μM in assaybuffer. The assay is initiated by the addition of 50 μl substrate perwell of the microfluor plate to give a final concentration of 10 μM.

Fluorescence readings (360 nM excitation, 460 nm emission) were taken attime 0 and then at 20 minute intervals. The assay is conducted at roomtemperature with a typical assay time of 3 hours.

Fluorescence vs time is then plotted for both the blank and collagenasecontaining samples (data from triplicate determinations is averaged). Atime point that provides a good signal (the blank) and that is on alinear part of the curve (usually around 120 minutes) is chosen todetermine IC₅₀ values. The zero time is used as a blank for eachcompound at each concentration and these values are subtracted from the120 minute data. Data is plotted as inhibitor concentration vs % control(inhibitor fluorescence divided by fluorescence of collagenasealone×100). IC₅₀ 's are determined from the concentration of inhibitorthat gives a signal that is 50% of the control.

If IC₅₀ 's are reported to be <0.03 μM then the inhibitors are assayedat concentrations of 0.3 μM, 0.03 μM, 0.03 μM and 0.003 μM.

Inhibition of Gelatinase (MMP-2)

Inhibition of gelatinase activity is assayed using theDnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂ substrate (10 μM) under thesame conditions as inhibition of human collagenase (MMP-1).

72 kD gelatinase is activated with 1 mM APMA (p-aminophenyl mercuricacetate) for 15 hours at 4° C. and is diluted to give a finalconcentration in the assay of 100 mg/ml. Inhibitors are diluted as forinhibition of human collagenase (MMP-1) to give final concentrations inthe assay of 30 μM, 3 μM, 0.3 μM and 0.03 μM. Each concentration is donein triplicate.

Fluorescence readings (360 nm excitation, 460 emission) are taken attime zero and then at 20 minutes intervals for 4 hours.

IC₅₀ 's are determined as per inhibition of human collagenase (MMP-1).If IC₅₀ 's are reported to be less than 0.03 μM, then the inhibitors areassayed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.003μM.

Inhibition of Stromelysin Activity (MMP-3)

Inhibition of stromelysin activity is based on a modifiedspectrophotometric assay described by Weingarten and Feder (Weingarten,H. and Feder, J., Spectrophotometric Assay for Vertebrate Collagenase,Anal. Biochem. 147, 437-440 (1985)). Hydrolysis of the thio peptolidesubstrate Ac-Pro-Leu-Gly-SCH CH₂ CH(CH₃)₂ !CO-Leu-Gly-OC₂ H₅ ! yields amercaptan fragment that can be monitored in the presence of Ellman'sreagent.

Human recombinant prostromelysin is activated with trypsin using a ratioof 1 μl of a 10 mg/ml trypsin stock per 26 μg of stromelysin. Thetrypsin and stromelysin are incubated at 37° C. for 15 minutes followedby 10 μl of 10 mg/ml soybean trypsin inhibitor for 10 minutes at 37° C.to quench trypsin activity.

Assays are conducted in a total volume of 250 μl of assay buffer (200 mMsodium chloride, 50 mM MES, and 10 mM calcium chloride, pH 6.0) in96-well microliter plates. Activated stromelysin is diluted in assaybuffer to 25 μg/ml. Ellman's reagent (3-Carboxy-4-nitrophenyl disulfide)is made as a 1M stock in dimethyl formamide and diluted to 5 mM in assaybuffer with 50 μl per well yielding at 1 mM final concentration.

10 mM stock solutions of inhibitors are made in dimethyl sulfoxide anddiluted serially in assay buffer such that addition of 50 μL to theappropriate wells yields final concentrations of 3 μM, 0.3 μM, 0.003 μM,and 0.0003 μM. All conditions are completed in triplicate.

A 300 mM dimethyl sulfoxide stock solution of the peptide substrate isdiluted to 15 mM in assay buffer and the assay is initiated by additionof 50 μl to each well to give a final concentration of 3 mM substrate.Blanks consist of the peptide substrate and Ellman's reagent without theenzyme. Product formation was monitored at 405 nm with a MolecularDevices UVmax plate reader.

IC₅₀ values were determined in the same manner as for collagenase.

Inhibition of MMP-13

Human recombinant MMP-13 is activated with 2 mM APMA (p-aminophenylmercuric acetate) for 1.5 hours, at 37° C. and is diluted to 400 mg/mlin assay buffer (50 mM Tris, pH 7.5, 200 mM sodium chloride, 5 mMcalcium chloride, 20 μM zinc chloride, 0.02% brij). Twenty-fivemicroliters of diluted enzyme is added per well of a 96 well microfluorplate. The enzyme is then diluted in a 1:4 ratio in the assay by theaddition of inhibitor and substrate to give a final concentration in theassay of 100 mg/ml.

10 mM stock solutions of inhibitors are made up in dimethyl sulfoxideand then diluted in assay buffer as per the inhibitor dilution schemefor inhibition of human collagenase (MMP-1): Twenty-five microliters ofeach concentration is added in triplicate to the microfluor plate. Thefinal concentrations in the assay are 30 μM, 3 μM, 0.3 μM and 0.03 μM.

Substrate (Dnp-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH₂) is prepared asfor inhibition of human collagenase (MMP-1) and 50 μl is added to eachwell to give a final assay concentration of 10 μM. Fluorescence readings(360 nM excitation; 450 emission) are taken at time 0 and every 5minutes for 1 hour.

Positive controls consist of enzyme and substrate with no inhibitor andblanks consist of substrate only.

IC₅₀ 's are determined as per inhibition of human collagenase (MMP-1).If IC₅₀ 's are reported to be less than 0.03 μM, inhibitors are thenassayed at final concentrations of 0.3 μM, 0.03 μM, 0.003 μM and 0.0003μM.

Inhibition of TNF Production

The ability of the compounds or the pharmaceutically acceptable saltsthereof to inhibit the production of TNF and, consequently, demonstratetheir effectiveness for treating diseases involving the production ofTNF is shown by the following in vitro assay:

Human mononuclear cells were isolated from anti-coagulated human bloodusing a one-step Ficoll-hypaque separation technique. The mononuclearcells were washed three times in Hanks balanced salt solution (HBSS)with divalent cations and resuspended to a density of 2×10⁶ /ml in HBSScontaining 1% BSA. Differential counts determined using the Abbott CellDyn 3500 analyzer indicated that monocytes ranged from 17 to 24% of thetotal cells in these preparations.

180 μ of the cell suspension was aliquoted into flate bottom 96 wellplates (Costar). Additions of compounds and LPS (100 ng/ml finalconcentration) gave a final volume of 200 μl. All conditions wereperformed in triplicate. After a four hour incubation at 37° C. in anhumidified CO₂ incubator, plates were removed and centrifuged (10minutes at approximately 250×g) and the supernatants removed and assayedfor TNFα using the R&D ELISA Kit.

For administration to humans for the inhibition of matrixmetalloproteinases or the production of tumor necrosis factor (TNF), avariety of conventional routes may be used including orally,parenterally and topically. In general, the active compound will beadministered orally or parenterally at dosages between about 0.1 and 25mg/kg body weight of the subject to be treated per day, preferably fromabout 0.3 to 5 mg/kg. However, some variation in dosage will necessarilyoccur depending on the condition of the subject being treated. Theperson responsible for administration will, in any event, determine theappropriate dose for the individual subject.

The compounds of the present invention can be administered in a widevariety of different dosage forms, in general, the therapeuticallyeffective compounds of this invention are present in such dosage formsat concentration levels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (and preferably corn, potato or tapioca starch), alginicacid and certain complex silicates, together with granulation binderslike polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administration,the active ingredient may be combined with various sweetening orflavoring agents, coloring matter or dyes, and, if so desired,emulsifying and/or suspending agents as well, together with suchdiluents as water, ethanol, propylene glycol, glycerin and various likecombinations thereof.

For parenteral administration (intramuscular, intraperitoneal,subcutaneous and intravenous use) a sterile injectable solution of theactive ingredient is usually prepared. Solutions of a therapeuticcompound of the present invention in either sesame or peanut oil or inaqueous propylene glycol may be employed. The aqueous solutions shouldbe suitably adjusted and buffered, preferably at a pH of greater than 8,if necessary and the liquid diluent first rendered isotonic. Theseaqueous solutions are suitable intravenous injection purposes. The oilysolutions are suitable for intraarticular, intramuscular andsubcutaneous injection purposes. The preparation of all these solutionsunder sterile conditions is readily accomplished by standardpharmaceutical techniques well known to those skilled in the art.

The present invention is illustrated by the following examples, but itis not limited to the details thereof.

EXAMPLE 1 2-(R)-N-Hydroxy-2- (-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyramide

To a solution of D-valine benzyl ester hydrochloride (2.4 grams, 10mmol) and triethylamine (2.5 grams, 3.5 mL, 25 mmol) in water (50 mL)and 1,4-dioxane (50 mL) is added 4-methoxybenzenesulfonyl chloride (2.3grams, 11 mmol). The mixture was stirred at room temperature for 1 hourand then most of the solvent was removed by evaporation under vacuum.The mixture was diluted with ethyl acetate and was washed successivelywith dilute hydrochloric acid solution, water and brine. The organicsolution was dried over magnesium sulfate and concentrated to leaveN-(4-methoxybenzenesulfonyl)-D-valine benzyl ester as a white solid, 3.6grams (97%); m.p. 92°-94° C.

N-(4-Methoxybenzenesulfonyl)-D-valine benzyl ester (1.50 grams, 4.0mmol) was added to a suspension of sodium hydride (0.1 grams, 4.2 mmol)in dry dimethylformamide (20 mL) and, after 30 minutes, tert-butylbromoacetate (0.8 mL, 4.2 mmol) was added. The resulting mixture wasstirred overnight at room temperature and was then quenched by additionof saturated ammonium chloride solution (3 mL). The dimethylformamidewas removed by evaporation under vacuum. The residue was taken up inethyl acetate and washed with water and brine. After drying overmagnesium sulfate, ethyl acetate was evaporated to leave an oil fromwhich 2-(R)-2-tert-butoxycarbonylmethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester, a clear oil (1.92 grams, 98%), was isolated usingflash chromatography on silica gel eluting with 15% ethyl acetate inhexane.

To a cold (0° C.) solution of 2-(R)-2-tert-butoxycarbonylmethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester (1.92 grams, 3.9 mmol) in methylene chloride (28 mL)was added trifluoroacetic acid (7 mL). The resulting solution wasallowed to warm to room temperature and was stirred overnight. Themethylene chloride and trifluoroacetic acid were evaporated under vacuumleaving 2-(R)-2-carboxymethyl(4-methoxybenzenesulfonyl)amino)!-3-methylbutyric acidbenzyl ester as a clear oil, 1.70 grams (100%).

To a solution of 2-(R)-2-carboxmethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acid benzylester (573 mg, 1.32 mmol) in methylene chloride (12 mL) were addedsequentially triethylamine (0.46 mL, 3.28 mmol), morpholine (0.127 mL,1.46 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (646 mg, 1.46 mmol). The mixture was stirred at roomtemperature overnight and then diluted with ethyl acetate. The solutionwas washed with 0.5N hydrochloric acid solution and brine, dried overmagnesium sulfate and concentrated under vacuum. The residue waschromatographed on silica gel using 40% ethyl acetate in hexaneaffording 2-(R)-2-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-oxoethyl)amino!-3-methylbutyricacid benzyl ester as a clear oil, 590 mg (89%).

To a solution of 2-(R)-2-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyricacid benzyl ester (590 mg, 1.17 mmol) in ethanal (50 mL) was added 10%palladium on activated carbon (200 mg). The mixture was agitated under 3atmospheres hydrogen in a Parr shaker for 2 hours. The catalyst wasremoved by filtration through nylon (pore size 0.45 μm) and the solventwas evaporated leaving 2-(R)-2-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyricacid as a white foam, 485 mg (100%).

To a solution of 2-(R)-2-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyricacid (485 mg, 1.17 mmol) in methylene chloride (12 mL) were addedsequentially triethylamine (0.52 mL, 3.71 mmol), O-benzylhydroxylaminehydrochloride (205 mg, 1.28 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(570 mg, 1.29 mmol). The mixture was stirred at room temperatureovernight and then diluted with ethyl acetate. The solution was washedsequentially with 0.5N hydrochloric acid solution, water, saturatedsodium hydrogen carbonate solution and brine, dried over magnesiumsulfate and concentrated under vacuum. The residue was chromatographedon silica gel using 20% hexane in ethyl acetate to afford2-(R)-N-benzyloxy-2- (4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyramide as a white foam,510 mg (84%).

To a solution of 2-(R)-N-benzyloxy-2-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyramide(510 mg, 0.98 mmol) in methanol (50 mL) was added 5% palladium onactivated carbon (120 mg). The mixture was agitated under 2 atmosphereshydrogen in a Parr shaker for 2 hours. The catalyst was removed byfiltration through nylon (pore size 0.45 μm) and the solvent wasevaporated leaving 2-(R)-N-hydroxy-2-(-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!-3-methylbutyramideas a white solid, 418 mg (99%); ¹ H NMR (CDCl₃): δ 10.3 (br s, 1H), 7.90(br s, 1H, overlapped), 7.86 (d, J=8.8 Hz, 2H, overlapped), 6.94 (d,J=8.8 Hz, 2H), 4.39 (d, J=17.1 Hz, 1H), 4.09 (d, J=17.1, 1H), 3.84 (s,3H), 3.80-3.48 (m, 9H), 2.20-1.95 (m, 1H), 0.82 (d, J=6.5 Hz, 3H), 0.45(d, J=6.5 Hz, 3H); MS (LSIMS): m/z 430 (M+H).

EXAMPLE 2 2-(R)-N-Hydroxy-2- (4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methylbutyramide

To a solution of N-(4-methoxybenzenesulfonyl)-D-valine benzyl ester (2.2grams, 5.83 mmol) in dry dimethylformamide (40 mL) were added cesiumcarbonate (2.3 grams, 7.1 mmol) and 1-iodo-3-butene (1.3 grams, 7.1mmol). The mixture was stirred at room temperature overnight and wasthen poured into water. The mixture was extracted twice with ether andthe combined ether extracts were washed with brine, dried over magnesiumsulfate and concentrated under reduced pressure. The residue was takenup in 20% ethyl acetate/hexane; starting materialN-(4-methoxybenzenesulfonyl)-D-valine benzyl ester (1.5 g) crystallizedfrom the mixture and was recovered by filtration. The filtrate wasconcentrated under vacuum and the residue was chromatographed on silicagel using 20% ethyl acetate/hexane as eluent to provide 2-(R)-2-but-3-enyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acid benzylester as a clear oil, 404 mg (16%).

To a mixture of 2-(R)-2-but-3-enyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acid benzylester (780 mg, 1.81 mmol) and ruthenium (III) chloride hydrate (10 mg,0.048 mmol) in acetonitrile (6 mL), carbon tetrachloride (6 mL) andwater (8 mL) was added sodium periodate (1.7 grams, 7.9 mmol). Afterstirring at room temperature for 2 hours, the mixture was diluted withmethylene chloride and filtered through diatomaceous earth. The organiclayer was separated, washed with dilute hydrochloric acid solution andbrine, dried over magnesium sulfate and concentrated to leave 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester as an oil, 710 mg (87%).

Alternatively, the intermediate 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester was prepared by the following higher yielding procedure:

N-(4-Methoxybenzenesulfonyl)-D-valine benzyl ester (18.8 grams, 49.8mmol) was added to a suspension of sodium hydride (1.3 grams, 54 mmol)in dry dimethylformamide (200 mL) and, after 1.5 hours, a solution ofallyl bromide (4.7 mL, 54 mmol) was added. The resulting mixture wasstirred overnight at room temperature and was then quenched by additionof saturated ammonium chloride solution. The dimethylformamide wasremoved by evaporation under vacuum. The residue was taken up in etherand washed with water and brine. After drying over magnesium sulfate,ether was evaporated to leave an oil from which 2-(R)-2-(4-methoxybenzenesulfonyl)prop-2-enylamino!-3-methylbutyric acid benzylester, a clear oil (18.1 grams, 87%), was isolated using flashchromatography on silica gel eluting with 10% ethyl acetate in hexaneand then 20% ethyl acetate in hexane.

To a 1M solution of borane/disulfide complex in methylene chloride (1.45mL, 2.9 mmol) was added a solution of 2-(R)-2-(4-methoxybenzenesulfonyl)prop-2-enylamino!-3-methylbutyric acid benzylester (3.6 grams, 8.6 mmol) in methylene chloride (8 mL). The solutionwas stirred at room temperature for 4 hours at which time more 1Msolution of borane/disulfide complex in methylene chloride (2.0 mL, 4.0mmol) was added. The mixture was stirred at room temperature overnightand was then added dropwise to a mechanically stirred solution ofchromium trioxide (5.1 grams, 51.6 mole) in acetic acid (31 mL) andwater (3.5 mL) while keeping the internal temperature between -5° C. and10° C. After stirring at room temperature overnight, the mixture wasdiluted with water and extracted with methylene chloride. The extractwas washed with brine, dried (magnesium sulfate) and concentrated. Theresidue was chromatographed on silica gel eluting successively withchloroform and 2% methanol in chloroform to afford 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl as an oil (2.42 grams, 63%).

To a solution of 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (710 mg, 1.58 mmol) in methylene chloride (15 mL) wereadded sequentially triethylamine (0.47 mL, 3.35 mmol), morpholine (0.15mL, 1.72 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (769 mg, 1.74 mmol). The mixture was stirred at roomtemperature overnight and then diluted with methylene chloride. Thesolution was washed with 0.5N hydrochloric acid solution and brine,dried over magnesium sulfate and concentrated under vacuum. The solidresidue was chromatographed on silica gel using 20% hexane in ethylacetate affording 2-(R)-2-(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methylbutyricacid benzyl ester as a clear oil, 725 mg (88%).

To a solution of 2-(R)-2-(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methylbutyricacid benzyl ester (725 mg, 1.40 mmol) in ethanol (35 mL) was added 10%palladium on activated carbon (50 mg). The mixture was agitated under 3atmospheres hydrogen in a Parr shaker for 3 hours. The catalyst wasremoved by filtration through nylon (pore size 0.45 pm) and the solventwas evaporated leaving 2-(R)-(2)-(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methyl-butyricacid as a white solid, 540 mg (90%).

To a solution of 2-(R)-2-(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methylbutyricacid (540 mg, 1.26 mmol) and 1-hydroxybenztriazole hydrate (205 mg, 1.33mmol) in dry dimethylformamide (12 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (289 mg,1.51 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride(350 mg, 5.04 mmol) and then triethylamine (1.0 mL, 7.17 mmol) wereadded. The mixture was stirred at room temperature overnight and thendiluted with ethyl acetate. The solution was washed sequentially withwater, 0.5N hydrochloric acid solution and brine. The solution was thendried over magnesium sulfate and concentrated under vacuum to leave awhite foam. The material was dissolved in toluene, filtered andconcentrated. The residue was triturated with ether to afford2-(R)-N-hydroxy-2(4-methoxybenzenesulfonyl)(3-morpholin-4-yl-3-oxopropyl)amino!-3-methylbutyramideas a solid, 200 mg (36%); ¹ H NMR (CDCl₃): δ 9.35 (br s, 1H), 7.73 (d,J=8.9 Hz, 2H), 6.95 (d, J=8.9 Hz, 2H), 3.86 (s, 3H), 3.83-3.73 (m, 1H),3.70-3.52 (m, 7H), 3.46-3.43 (m, 2H), 3.41-3.29 (m, 1H), 2.92-2.69 (m,2H), 2.30-2.17 (m, 1H), 0.84 (d, J=6.5 Hz, 3H), 0.41 (d, J=6.5 Hz, 3H);MS (particle beam): m/z 444 (M+H), 428, 383, 329; HRMS calculated forC₁₉ H₃₀ N₃ O₇ S (M+H): 444.1804, Found: 464.1818.

The title compounds of Examples 3-6 were prepared by a method analogousto that described in Example 2 using 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester as the starting material which is coupled with the amineindicated.

EXAMPLE 3 2-(R)-2-(2-Benzylcarbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide

Coupled with benzylamine; ¹ H NMR (DMSO-d₆): δ 10.72 (s, 1H), 8.89 (s,1H), 8.39 (m, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.32-7.21 (m, 5H), 7.05 (d,J=9.0 Hz, 2H), 4.21 (d, J=5.9 Hz, 2H), 4.02-3.87 (m, 1H), 3.82 (s, 3H),3.63 (d, J=10.8 Hz, 1H), 3.29-3.17 (m, 1H), 2.71-2.57 (m, 1H), 2.52-2.40(m, 1H), 2.06-1.94 (m, 1H), 0.77 (d, J=6.6 Hz, 3H), 0.74 (d, J=6.5 Hz,3H); MS (LSIMS): m/z 464 (M+H); HRMS calculated for C₂₂ H₃₀ N₃ O₆ S(M+H): 464.1855. Found: 464.1832.

EXAMPLE 4 2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl) (2-(pyridin-3-ylmethyl)carbamoyl!ethyl)amino)-3-methylbutyramide

Coupled with 3-pyridylmethylamine: ¹ H NMR (DMSO-d₆): δ 10.72 (s, 1H),8.89 (s, 1H), 8.49-8.42 (m, 3H), 7.73 (d, J=8.9 Hz, 2H), 7.63-7.60 (m,1H), 7.32 (dd, J=4.8, 7.8 Hz, 1H), 7.05 (d, J=8.9 Hz, 2H), 4.23 (d,J=5.8 Hz, 2H), 4.00-3.88 (m, 1H), 3.81 (s, 3H), 3.62 (d, J=10.8 Hz, 1H),3.27-3.17 (m, 1H), 2.69-2.58 (m, 1H), 2.52-2.41 (m, 1H), 2.07-1.94 (m,1H), 0.76 (d, J=6.5 Hz, 3H), 0.72 (d, J=6.4 Hz, 3H); MS (LSIMS): m/z 465(M+H).

EXAMPLE 5 2-(R)-N-Hydroxy-2-( 4-methoxybenzenesulfonyl!2-(methylpyridin-3-ylmethylcarbamoyl)ethyl!amino)-3-methylbutyramide

Coupled with 3-(N-methylaminomethyl)pyridine: ¹ H NMR (DMSO-d₆): δ 10.75(br s, 1H), 8.92 (s, 1H), 8.52-8.29 (m, 2H), 7.75 (d, J=8.8 Hz, 1.4H),7.67 (d, J=8.8 Hz, 0.6H), 7.62-7.58 (m, 1H), 7.42-7.32 (m, 1H), 7.06 (d,J=8.8 Hz, 1.4H), 7.01 (d, J=8.8 Hz, 0.6H), 4.55-4.41 (m, 2H), 3.94-3.82(m, 1H), 3.81 (s, 2.1H), 3.80 (s, 0.9H), 3.68-3.60 (m, 1H), 3.33-3.19(m, 1H), 2.90-2.50 (m, 2H), 2.88 (s, 2.1H overlapped), 2.79 (s, 0.9H),2.05-1.80 (m, 1H), 0.79-0.63 (m, 6H): MS (thermospray): m/z 479 (M+H),364.

EXAMPLE 6 4-(3-(1-(R)-1-Hydroxycarbamoyl-2-methylpropyl)(4-methoxybenzenesulfonyl)amino!propionyl)pierazine-1-carboxylic acid, tert-butyl ester

Coupled with tert-butyl-1-piperazinecarboxylate: ¹ H NMR (DMSO-d₆): δ10.77 (br s, 1H), 8.93 (s, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 3.90-3.80 (m, 1H), 3.82 (s, 3H, overlapped), 3.64 (d, J=10.8Hz, 1H), 3.60-3.16 (m, 9H), 2.80-2.71 (m, 1H), 2.59-2.47 (m, 1H),2.03-1.91 (m, 1H), 1.39 (s, 9H), 0.77 (d, J=6.5 Hz, 3H), 0.71 (d, J=6.5,3H); MS (thermospray): m/z 543 (M+H), 443, 382, 328.

EXAMPLE 7 2-(R)-N-Hydroxy-2- (4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-1-ylpropyl)amino!-3-methylbutyramide hydrocholoride

A solution of 4-(3-(1-(R)-1-hydroxycarbamoyl-2-methylpropyl)(4-methoxybenzenesulfonyl)amino!propionyl)piperazine-1-carboxylicacid, tert-butylester Example 6! (430 mg, 0.79 mmol) in methylenechloride (11 mL) was cooled to 0° C. Hydrogen chloride gas was thenbubbled through the solution for about 0.5 minute. The solution wasallowed to warm to room temperature with stirring over 1 hour. Volatileswere removed by evaporation and the residue was filtered washing withmethylene chloride to collect solid 2-(R)-N-hydroxy-2-(4-methoxybenzenesulfonyl)(3-oxo-3-piperazin-1-ylpropyl)amino!-3-methylbutyramidehydrochloride, 375 mg (99%). ¹ H NMR (DMSO-d₆): δ 10.78 (br s, 1H), 9.16(br s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.07 (d, J=8.9 Hz, 2H), 3.82 (s,3H), 3.62 (br s, 4H), 3.38-3.18 (m, 1H), 3.16-3.07 (br s, 2H), 3.07-2.98(br s, 2H), 2.83-2.73 (m, 1H), 2.65-2.53 (m, 1H), 2.06-1.90 (m, 1H),0.76 (d, J=6.5 Hz, 3H), 0.72 (d, J=6.5 Hz, 3H). A broad water peakbetween δ 4.0 and 3.5 obscured some signals from this compound; MS(thermospray): m/z 443 (M+H), 382, 328.

EXAMPLE 8 2-(R)-2-(Benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide

To a solution of 2-(R)-2-carboxymethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (example 1) (905 mg, 2.08 mmol) in methylene chloride (18mL) were added sequentially triethylamine (0.72 mL, 5.14 mmol),benzylamine (0.25 mL, 2.29 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(1.01 grams, 2.28 mmol). The mixture was stirred at room temperatureovernight and then diluted with ethyl acetate. The solution was washedwith 0.5N hydrochloric acid solution and brine, dried over magnesiumsulfate and concentrated under vacuum. The residue was chromatographedon silica gel using a 2:5:16 ratio of methylene chloride/ethylacetate/hexane affording 2-(R)-2-(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester as a clear oil, 933 mg (86%).

To a solution of 2-(R)-2-(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester (933 mg, 1.17 mmol) in ethanol (50 mL) was added 10%palladium on activated carbon (85 mg). The mixture was agitated under 3atmospheres hydrogen in a Parr shaker for 4 hours. The catalyst wasremoved by filtration through nylon (pore size 0.45 μm) and the solventwas evaporated leaving 2-(R)-2-(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid as a white foam, 755 mg (98%).

To a solution of 2-(R)-2(benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid (655 mg, 1.51 mmol) and 1-hydroxybenztriazole hydrate (224 mg, 1.46mmol) in dry dimethylformamide (15 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (316 mg,1.65 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride(416 mg, 6.0 mmol) and then N-methylmorpholine (0.99 mL, 9.0 mmol) wereadded. The mixture was stirred at room temperature overnight and thendiluted with ethyl acetate. The solution was washed sequentially withwater, 0.5N hydrochloric acid solution and brine. The solution was thendried over magnesium sulfate and concentrated under vacuum to leave awhite foam which was chromatographed on silica gel eluting with ethylacetate to afford 2-(R)-2-(benzylcarbamoylmethyl)(4-methoxybenzene-sulfonyl)amino!-N-hydroxy-3-methylbutyramideas a white foam, 570 mg (84%); ¹ H NMR (DMSO-d₆): δ 10.75 (br s, 1H),8.90 (s, 1H), 8.47 (m, 1H), 7.85 (d, J=8.9 Hz, 2H), 7.83-7.19 (m, 5H),7.04 (d, J=8.9 Hz, 2H), 4.37 (d, J=11.4 Hz, 1H), 4.28 (d, J=5.9 Hz, 2H),3.89 (d, J=11.4 Hz, 1H), 3.82 (s, 3H), 3.45 (d, J=10.3 Hz, 1H),1.90-1.79 (m, 1H), 0.73 (d, J=6.3 Hz, 6H); MS (LSIMS): m/z 450 (M+H).

EXAMPLE 9 2-(R)-2-(Benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide

To a solution of 2-(R)-2-carboxymethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (Example 1) (1.05 grams, 2.41 mmol) in methylene chloride(20 mL) were added sequentially triethylamine (0.84 mL, 6.0mmol),N-benzylmethylamine (0.34 mL, 2.63 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(1.17 grams, 2.69 mmol). The mixture was stirred at room temperatureovernight and then diluted with ethyl acetate. The solution was washedwith 0.5N hydrochloric acid solution and brine, dried over magnesiumsulfate and concentrated under vacuum. The residue was chromatographedon silica gel using 35% ethyl acetate in hexane (plus a small amount ofmethylene chloride to load the sample on the column) affording 2-(R)-2-benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester as a clear oil, 1.14 grams (88%).

To a solution of 2-(R)-2-(benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester (1.14 grams, 2.12 mmol) in ethanol (100 mL) was added10% palladium on activated carbon (400 mg). The mixture was agitatedunder 3 atmospheres hydrogen in a Parr shaker for 3 hours. The catalystwas removed by filtration through nylon (pore size 0.45 μm) and thesolvent was evaporated leaving 2-(R)-2-(benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid as a white foam, 902 mg (95%).

To a solution of 2-(R)-2-(benzylmethylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid (902 mg, 2.01 mmol) in methylene chloride (20 mL) were addedsequentially triethylamine (0.90 mL, 6.42 mmol), O-allylhydroxylaminehydrochloride (242 mg, 2.21 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(978 mg, 2.21 mmol). The mixture was stirred at room temperatureovernight and then diluted with ethyl acetate. The solution was washedwith 0.5N hydrochloric acid solution and brine, dried over magnesiumsulfate and concentrated under vacuum. The residue was chromatographedon silica gel using 40% hexane in ethyl acetate to afford2-(R)-N-allyloxy-2-(benzylmethylcarbamoylmethyl)(4-methoxy-benzenesulfonyl)amino!-3-methylbutyramideas an oil, 1.008 grams (100%).

To a solution of 2-(R)-N-allyloxy-2-(benzylmethyl-carbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyramide(500 mg, 0.99 mmol) in methylene chloride (40 mL) was addedbis(triphenylphosphine)palladium (II) chloride (280 mg, 0.4 mmol) andthen, dropwise, tributyltinhydride (0.43 mL, 2.2 mmol). The solution wasstirred at room temperature for 1 hour, diluted with methylene chloride,washed with 1N hydrochloric acid solution, dried over magnesium sulfateand concentrated. The residue was taken up in ethyl acetate and filteredto remove a solid. After concentration, the filtrate was chromatographedon silica gel eluting with chloroform and then 2% methanol in chloroformto afford 2-(R)-2-(benzylmethylcarbamoylmethyl)(4-methoxybenzene-sulfonyl)amino!-N-hydroxy-3-methylbutyramideas a white solid (340 mg, 74%). ¹ H NMR (DMSO-d₆): δ 10.66 (br s, 1H),8.87 (br s, 0.6 H), 8.84 (s, 0.4 H), 7.91 (d, J=8.9 Hz, 1.2 H), 7.78 (d,J=8.9 Hz, 0.8 H), 7.43-7.21 (m, 5H), 7.05 (d, J=8.9 Hz, 1.2 H), 7.00 (d,J=8.9 Hz, 0.8 H) 4.72 (d, J=17.7 Hz, 0.4 H), 4.70 (d, J=17.7 Hz, 0.6 H),4.59-4.42 (m, 1H), 4.25 (d, J=17.8 Hz, 0.6H), 4.07 (d, J=17.7 Hz, 0.4H),3.82 (s, 3H), 3.46-3.40 (m, 1H), 2.91 (s, 1.8H), 2.83 (s, 1.2 H),1.92-1.70 (m, 1H), 0.75-0.69 (m, 6H); MS (thermospray): m/z 464 (M+H),307, 239.

The title compounds of Examples 10-11 were prepared by a methodanalogous to that described in Example 9 using 2-(R)-2-carboxymethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (Example 1) as the starting material which is coupled withthe amine indicated.

EXAMPLE 10 2-(R)-N-Hydroxy-2-( 4-methoxybenzenesulfonyl!-(2-morpoholin-4-ylethylcarbamoyl)methyl!amino)-3-methylbutyramide

Coupled with 4-(2-aminoethyl)morpholine: ¹ H NMR (DMSO-d₆): δ 10.74 (brs, 1H), 8.90 (br s, 1H), 7.84 (br s, 1H, overlapped), 7.84 (d, J=8.8 Hz,2H), 7.06 (d, J=8.8 Hz, 2H), 4.33 (d, J=17.5 Hz, 1H), 3.83 (s, 3H), 3.78(d, J=17.5 Hz, 1H), 3.57-3.54 (m, 4H), 3.49 (d, J=10.2 Hz, 1H),3.28-3.06 (m, 2H), 2.34-2.30 (m, 6H), 1.93-1.77 (m, 1H), 0.77-0.74 (m,6H).

EXAMPLE 11 2-(R)-N-Hydroxy-2-(4-methoxybenzenesulfonyl)(2-oxo-2-pyrrolidin-1-ylethyl)amino!-3-methylbutyramide

Coupled with pyrrolidine: ¹ H NMR (CD₃ OD): δ 7.90 (d, J=8.9 Hz, 2H),7.04 (d, J=8.9 Hz, 2H), 4.50 (d, J=17.6 Hz, 1H), 4.15 (d, J=17.6 Hz,1H), 3.87 (s, 3H), 3.56-3.39 (m, 5H), 2.07-1.82 (m, 5H), 0.83 (d, J=6.6Hz, 3H), 0.73 (d, J=6.6 Hz, 3H); MS (thermospray): m/z 414 (M+1); HRMScalculated for C₁₈ H₂₈ N₃ O₆ S (M+H): 414.1699. Found 414.1703.

EXAMPLE 12 2-Dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methyl-butyramide

A solution of 2-(R)-2-carboxymethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (Example 1) (1.89 grams, 4.34 mmol) in thionyl chloride (25mL) was heated at reflux for 1 hour. After cooling, the excess thionylchloride was evaporated. The residue was taken up in methylene chloride(50 mL) and the solution was cooled in an ice bath. Dimethylamine gaswas slowly bubbled through the solution for 1 hour. After evaporation ofthe solvent, the residue was taken up in ethyl acetate, washed with 1Nhydrochloric acid solution, water and brine, dried over magnesiumsulfate and concentrated to leavedimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyricacid benzyl ester as an oil, 1.77 grams (88%).

To a solution ofdimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyricacid benzyl ester (1.77 grams, 3.83 mmol) in ethanol (100 mL) was added10% palladium on activated carbon (644 mg). The mixture was agitatedunder 3 atmospheres hydrogen in a Parr shaker for 1.5 hours. Thecatalyst was removed by filtration through nylon (pore size 0.45 μm) andthe solvent was evaporated leavingdimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyricacid as a white foam, 1.42 grams (100%).

To a solution ofdimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyricacid (1.42 grams, 3.81 mmol) and 1-hydroxybenztriazole hydrate (687 mg,4.48 mmol) in dry dimethylformamide (7 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (974 mg,5.08 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride(1.17 grams, 16.8 mmol) and then N-methylmorpholine (2.8 mL, 25.5 mmol)were added. The mixture was stirred at room temperature overnight andthen concentrated under vacuum. The residue was taken up in ethylacetate and the resulting solution was washed sequentially with water,0.5N hydrochloric acid solution and brine. The solution was then driedover magnesium sulfate and concentrated under vacuum to leave an oilwhich was chromatographed on silica gel eluting successively with ethylacetate, 5% methanol in chloroform and 10% methanol in chloroform toafford 2-dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramideas a white solid, 390 mg (26%). ¹ H NMR (DMSO-d₆): δ 10.70 (br s, 1H),8.89 (s, 1H), 7.80 (d, J=8.9 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H), 4.62 (d,J=17.7 Hz, 1H), 4.14 (d, J=17.7 Hz, 1H), 3.84 (s, 3H), 3.40 (d, J=10.4Hz, 1H), 2.97 (s, 3H), 2.82 (s, 3H), 1.88-1.72 (m, 1H), 0.72 (d, J=6.5Hz, 6H); MS (thermospray): m/z 388 (M+1); HRMS calculated for C₁₆ H₂₆ N₃O₆ S (M+H): 388.1542 Found: 388.1592.

EXAMPLE 13 2-(R)-2-N-Hydroxy-2-((4-methoxybenzenesulfonyl) ((pyridin-3-ylmethyl)carbamoyl!methyl)amino)-3-methylbutyramide

2-(R)-N-Hydroxy-2-((4-methoxybenzenesulfonyl)((pyridin-3-ylmethyl)carbamoyl!methyl)amino)-3-methylbutyramide wasprepared by a procedure similar to that of Example 12 starting with2-(R)-2- carboxymethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester (Example 1) and coupling this to 3-pyridylmethylaminevia the acid chloride. ¹ H NMR (CD₃ OD): δ 8.55-8.53 (m, 1H), 8.43-8.40(m, 1H), 7.907.82 (m, 1H, overlapped), 7.86 (d, J=8.9 Hz, 2H), 7.40 (dd,J=4.8, 7.8 Hz, 1H), 7.04 (d, J=8.9 Hz, 2H), 4.50 (d, J=17.5 Hz, 1H),4.39 (d, J=17.5 Hz, 1H), 4.32 (d, J=17.7 Hz, 1H), 4.02 (d, J=17.7 Hz,1H), 3.87 (s, 3H), 3.60 (d, J=10.3 Hz, 1H), 2.08-1.93 (m, 1H), 0.85 (d,J=6.5 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H); MS (thermospray): m/z 451 (M+H),336, 320.

EXAMPLE 14 N-Hydroxy- (4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!acetamide

To a solution of iminoacetic acid disodium salt monohydrate (5.0 grams,25.6 mmol) in dioxane (50 ml) and water (50 ml) was added triethylamine(5.3 ml, 38 mmol) followed by 4-methoxybenzenesulfonyl chloride (5.8grams, 28.0 mmol). The mixture was stirred overnight at room temperatureand diluted with methylene chloride. The solution was washed with 1Nhydrochloric acid solution, water and brine, dried over magnesiumsulfate and concentrated under vacuum leavingcarboxymethyl(4-methoxybenzenesulfonyl)amino!acetic acid as a whitesolid, 3.83 grams (49%).

Carboxymethyl(4-methoxybenzenesulfonyl)amino!acetic acid (0.5 grams,1.65 mmol) in acetic anhydride (15 mL) was dissolved in acetic anhydrideby gentle warming. The resulting solution was stirred at roomtemperature overnight. The acetic anhydride was removed by evaporationunder vacuum; the residue was dissolved in methylene chloride andmorpholine (0.16 mL, 1.82 mmol) was added. The mixture was stirredovernight at room temperature and then concentrated under vacuum. Theresidue was dissolved in ethyl acetate, washed with 1N hydrochloric acidsolution, water and brine, dried over magnesium sulfate and concentratedto afford(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!acetic acidas an oil, 0.33 grams (54%).

To a solution of (4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!acetic acid (0.33 grams, 0.89 mmol) in methylene chloride (10 mL)were added sequentially triethylamine (0.43 mL, 3.1 mmol),O-benzylhydroxylamine hydrochloride (0.15 grams, 0.94 mmol) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(0.43 grams, 0.97 mmol). The mixture was stirred at room temperatureovernight and then diluted with ethyl acetate. The solution was washedsequentially with 0.5N hydrochloric acid solution, water and brine,dried over magnesium sulfate and concentrated under vacuum. The residuewas chromatographed on silica gel using ethyl acetate to affordN-benzyloxy-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!acetamideas a white solid, 0.33 grams (78%).

To a solution of N-benzyloxy-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!acetamide(0.33 grams, 0.69 mmol) in methanol (35 mL) was added 5% palladium onactivated carbon (85 mg). The mixture was agitated under 2 atmosphereshydrogen in a Parr shaker for 1.5 hours. The catalyst was removed byfiltration through nylon (pore size 0.45 μm) and the solvent wasevaporated. The residue was chromatographed on silica gel eluting with5% methanol in methylene chloride to afford N-methoxy-(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino!acetamideas a white solid, 65 mg (24%); ¹ H NMR (CD₃ OD): δ 7.82 (d, J=9.0 Hz,2H), 7.08 (d, J=9.0 Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H),3.68-3.64 (m, 4H), 3.581-3.50 (m, 4H); MS (thermospray): m/z 388 (M+1),387 (M); HRMS calculated for C₁₆ H₂₂ N₃ O₇ S (M+H): 388.1178, Found338.1180.

The title compounds of Examples 15-16 were prepared by a methodanalogous to that described in Example 14 usingcarboxymethyl(4-methoxybenzenesulfonyl)amino!acetic acid as the startingmaterial which, after treatment with acetic anhydride, is coupled withthe amine indicated.

EXAMPLE 15 N-Hydroxy-(4-methoxybenzenesulfonyl)(2-oxo-2-pyrrolidin-1-ylethyl)amino!acetamide

Coupled with pyrrolidine: ¹ H NMR (DMSO-d₆): δ 11.26 (br s, 1H), 8.89(s, 1H), 7.81 (d, J=8.9 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H), 4.09 (s, 2H),3.85 (s, 3H), 3.74 (s, 2H), 3.45-3.25 (m, 4H), 1.93-1.72 (m, 4H); MS(thermospray): m/z 372 (M+1): Analysis calculated for C₁₅ H₂₁ N₃ O₆ S:C, 48.51; H, 5.70; N, 11.31. Found: C, 48.51; H, 5.82; N, 11.24.

EXAMPLE 16 2-Dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino!-N-hydroxyacetamide

Coupled with dimethylamine: mp: 170° C. (dec.); ¹ H NMR (DMSO-d₆): δ10.69 (br s, 1H), 8.88 (s, 1H), 7.91 (d, J=8.9 Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 4.19 (s, 2H), 3.85 (s, 3H), 3.73 (s, 2H), 2.94 (s, 3H), 2.84(s, 3H); MS (thermospray): m/z 346 (M+1); Analysis calculated for C₁₃H₁₉ N₃ O₆ S: C, 45.21; H, 5.55 N, 12.17. Found: C, 44.93, H, 5.61; N,12.03.

EXAMPLE 17 2-(R)-2-(2-Carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide

To a solution of 2-(R)-2-(2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (example 2) (900 mg., 2.0 mmol) in methylene chloride (10mL) was added thionyl chloride (0.16 mL, 2.2 mmol). The reaction mixturewas stirred for 1.5 hours at room temperature and then concentrated invacua. After dissolving the residue in methylene chloride (10 mL),ammonia gas was bubbled through the solution for 0.5 minutes. Thesolution was stirred at room temperature overnight and was concentratedunder vacuum. Flash chromatography of the residue on silica gel elutingwith 2% methanol in chloroform provided 2-(R)-2-(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyricacid benzyl ester as a clear oil (275 mg, 31%).

To a solution of 2-(R)-2-(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyricacid benzyl ester (275 mg, 0.61 mmol) in ethanol (15 mL) was added 10%palladium on activated carbon (30 mg). The mixture was agitated under 3atmospheres hydrogen in a Parr shaker for 5 hours. The catalyst wasremoved by filtration through diatomaceous earth and the solvent wasevaporated leaving 2-(R)-2-(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyricacid as a white foam, 211 mg (96%).

To a solution of 2-(R)-2-2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyricacid (205 mg, 0.57 mmol) and 1-hydroxybenztriazole hydrate (85 mg, 0.55mmol) in dry dimethylformamide (5 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (120 mg,0.63 mmol). After stirring for 30 minutes, hydroxylamine hydrochloride(158 mg, 2.3 mmol) and then N-methylmorpholine (0.37 mL, 3.4 mmol) wereadded. The mixture was stirred at room temperature overnight and thendiluted with ethyl acetate. The solution was washed with water andbrine. The solution was then dried over magnesium sulfate andconcentrated under vacuum to leave an oil which was chromatographed onsilica gel eluting with 2% methanol in chloroform to afford 2-(R)-2-(2-carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramideas a white solid, 45 mg (21%); ¹ H NMR (DMSO-d₆): δ 10.74 (br s, 1H),8.91 (br s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.33 (br s, 1H), 7.07 (d, J=8.8Hz, 2H), 6.79 (br s, 1H), 3.93-3.82 (m, 1H, overlapped), 3.83 (s, 3H),3.64 (d, J=10.7 Hz, 1H), 3.25-3.12 (m, 1H), 2.62-2.48 (m, 1H), 2.42-2.30(m, 1H), 2.06-1.94 (m, 1H), 0.79 (d, J=6.6 Hz, 3H), 0.76 (d, J=6.6 Hz,3H); MS (thermospray): m/z 374 (M+H).

EXAMPLE 18 2-(R)-2-(2-tert-Butoxycarbonylethyl)(4-methoxybenzenesulfonyl)-amino!-N-hydroxy-3-methylbutyramide

A solution of N,N-dimethylformamide di-tert-butyl acetal (1.9 mL, 7.9mmol) in toluene (15 mL) was added dropwise to a solution of 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-3-methylbutyric acidbenzyl ester (example 2) 900 mg, 2.0 mmol) in toluene at 80° C. Afterheating for 2 hours at 80° C., the mixture was cooled and concentratedto leave an amber oil which was chromatographed on silica gel elutingwith chloroform to afford (2-(R)-2-(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester as an oil, 3.75 mg (37%).

To a solution of 2-(R)-2-(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid benzyl ester (370 mg, 0.73 mmol) in ethanol (20 mL) was added 10%palladium on activated carbon (40 mg). The mixture was agitated under 3atmospheres hydrogen in a Parr shaker for 5 hours. The catalyst wasremoved by filtration through diatomaceous earth and the solvent wasevaporated leaving 2-(R)-2-(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid as a white foam, 30 mg (100%).

To a solution of 2-(R)-2-(2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino!-3-methylbutyricacid (303 mg, 0.73 mmol) and 1-hydroxybenztriazole hydrate (108 mg, 0.70mmol) in dry dimethylformamide (10 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg,0.80 mmol). After stirring for 45 minutes, hydroxylamine hydrochloride(203 mg, 2.9 mmol) and then N-methylmorpholine (0.48 mL, 4.4 mmol) wereadded. The mixture was stirred at room temperature overnight and thenconcentrated under vacuum. The residue was chromatographed on silica geleluting with 2% methanol in chloroform and again with 10% ethyl acetatein hexane to afford 2-(R)-2- (2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide as a whitefoam, 135 mg (43%); ¹ H NMR (DMSO-d₆): δ 10.77 (br s 1H), 7.74 (d, J=8.9Hz, 2H), 7.08 (d, J=8.9 Hz, 2H), 3.93-3.82 (m, 1H, overlapped), 3.83 (s,3H), 3.64 (d, J=10.8 Hz, 1H), 3.26-3.14 (m, 1H), 2.70-2.60 (m, 1H),2.50-2.38 (m, 1H), 2.04-1.91 (m, 1H), 1.38 (s, 9H), 0.78 (d, J=6.5 Hz,3H), 0.72 (d, J=6.5 Hz, 3H); MS (thermospray): m/z 431 (M+H), 375, 314.

EXAMPLE 19 2-(R)-2- 2-Carboxyethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide

To a solution of 2-(R)-2-2-tert-butoxycarbonylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide(example 18) (100 mg, 0.23 mmol) in methylene chloride (1 mL) at 0° C.was added trifluoroacetic acid (1 mL). The mixture was allowed to warmto room temperature while stirring overnight. After evaporation of thetrifluoroacetic acid and methylene chloride, the residue waschromatographed on silica gel eluting with 5% methanol in chloroform.Concentration of the appropriate fractions afforded 2-(R)-2-2-carboxyethyl(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramideas a white solid, 35 mg (41%). ¹ H NMR (DMSO-d₆): δ 10.79 (br s,1H),8.97 (br s, 1H), 7.76 (d, J=8.9 Hz, 2H), 7.09 (d, J=8.9 Hz, 2H),3.95-3.82 (m, 1H, overlapped), 3.84 (s, 3H), 3.66 (d, J=10.8 Hz, 1H),3.30-3.20 (m, 1H), 2.73-2.62 (m, 1H), 2.50-2.40 (m, 1H), 2.07-1.94 (m,1H), 0.80 (d, J=6.5 Hz, 3H), 0.74 (d, J=6.5 Hz, 3H); MS (thermospray):m/z 375 (M+H), 314.

We claim:
 1. A compound of the formula ##STR9## or the pharmaceuticallyacceptable salts thereof, wherein n is 1 to 6:X is hydroxy, (C₁-C₆)alkoxy or NR¹ R² wherein R¹ and R² are each independently selectedfrom the group consisting of hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl, (C₆-C₁₀)aryl(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl, (C₆ -C₁₀)aryl(C₆-C₁₀)aryl(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl, (C₃ -C₆)cycloalkyl(C₁-C₆)alkyl, R⁵ (C₂ -C₆)alkyl, (C₁ -C₅)alkyl(CHR⁵)(C₁ -C₆)alkyl wherein R⁵is hydroxy, (C₁ -C₆)acyloxy, (C₁ -C₆)alkoxy (C₁ -C₆)acylamino, (C₁-C₆)alkylthio, (C₆ -C₁₀)arylthio, (C₁ -C₁₀)alkylsulfinyl, (C₆-C₁₀)arylsulfinyl, (C₁ -C₆)alkylsulfoxyl, (C₆ -C₁₀)arylsulfoxyl, amino,(C₁ -C₆)alkylamino, ((C₁ -C₆)alkyl)₂ amino; and CH(R⁷)COR⁸ wherein R⁷ ishydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₁-C₆)alkylthio(C₁ -C₆)alkyl, (C₆ -C₁₀)arylthio(C₁ -C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁-C₆)alkylsulfonyl(C₁ C₆)alkyl, (C₆ -C₁₀)arylsulfonyl(C₁ -C₆)alkyl,hydroxy(C₁ -C₆)alkyl, amino(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino(C₁-C₆)alkyl, ((C₁ -C₆)alkyl)₂ amino(C₁ -C₆)alkyl, R⁹ R¹⁰ NCO(C₁ -C₆)alkylor R⁹ OCO(C₁ -C₆)alkyl wherein R⁹ and R¹⁰ are each independentlyselected from the group consisting of hydrogen, (C₁ -C₆)alkyl, and (C₆-C₁₀)aryl(C₁ -C₆)alkyl and R⁸ is R¹¹ O or R¹¹ R¹² N wherein R¹¹ and R¹²are each independently selected from the group consisting of hydrogen,(C₁ -C₆)alkyl, and (C₆ -C₁₀)aryl(C₁ -C₆)alkyl; R³ and R⁴ are eachindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁ -C₆)alkyl, (C₁ -C₆)alkyl(difluoromethylene), (C₁ -C₃)alkyl(difluoromethylene)(C₁ -C₃)alkyl, (C₆-C₁₀)aryl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl, (C₆-C₁₀)aryl(C₆ -C₁₀)aryl(C₁ -C₆)alkyl (C₃ -C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁ -C₆)alkyl, hydroxy(C₁ -C₆)alkyl, (C₁ -C₆)acyloxy(C₁-C₆)alkyl, (C₁ -C₆)alkoxy(C₁ -C₆)alkyl, (C₁ -C₆)acylamino(C₁ -C₆)alkyl,(C₆ -C₁₀)aryl (C₁ -C₆)alkoxy(C₁ -C₆)alkyl, (C₁ -C₆)alkylthio(C₁-C₆)alkyl, (C₆ -C₁₀)arylthio(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfinyl(C₁-C₆)alkyl, (C₆ -C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁ -C₆)alkylsulfonyl(C₁-C₆)alkyl, (C₆ -C₁₀)arylsulfonyl(C₁ -C₆)alkyl, amino(C₁ -C₆)alkyl, (C₁-C₆)alkylamino(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino)₂ (C₁ -C₆)alkyl, R¹³CO(C₁ -C₆)alkyl wherein R¹³ is R²⁰ O or R²⁰ R²¹ N wherein R²⁰ and R²¹are each independently selected from the group consisting of hydrogen,(C₁ -C₆)alkyl, or (C₆ -C₁₀)aryl(C₁ -C₆)alkyl; or R³ and R⁴ or R²⁰ andR²¹ may be taken together to form a (C₃ -C₆)cycloalkyl, oxacyclohexyl,or thiocyclohexyl; and Ar is (C₆ -C₁₀)aryl, (C₁ -C₆)alkyl(C₆ -C₁₀)aryl,(C₁ -C₆)alkoxy (C₆ -C₁₀)aryl, ((C₁ -C₆)alkoxy)₂ (C₆ -C₁₀)aryl, or (C₆-C₁₀)aryloxy(C₆ -C₁₀)aryl; with the proviso that when either R¹ or R² isCH(R⁷)COR⁸ wherein R⁷ and R⁸ are as defined above, the other R¹ or R² ishydrogen, (C₁ -C₆)alkyl or benzyl.
 2. A compound according to claim 1,wherein n is
 2. 3. A compound according to claim 1, wherein Ar is4-methoxyphenyl or 4-phenoxyphenyl.
 4. A compound according to claim 1,2 or 3, wherein either R³ or R⁴ is not hydrogen.
 5. A compound accordingto claim 1, wherein n is 1 and either R¹ or R² is hydrogen.
 6. Acompound according to claim 4, wherein X is hydroxy, Ar is4-methoxyphenyl or 4-phenoxyphenyl.
 7. A compound according to claim 4,wherein X is alkoxy, Ar is 4-methoxyphenyl or 4-phenoxyphenyl.
 8. Acompound according to claim 1, wherein Ar is 4-methoxyphenyl or4-phenoxyphenyl and R³ and R⁴ are taken together to form (C₃-C₆)cycloalkanyl, oxacyclohexanyl, or thiocyclohexanyl.
 9. A compoundaccording to claim 1, wherein said compound is selected from the groupconsisting of:2-(R)-2-(2-Benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide;2-(R)-2-(Benzylcarbamoylmethyl)(4-methoxybenzenesulfonyl)amino!N-hydroxy-3-methylbutyramide;2-(R)-2-(2-Carboxyethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide;(2-Carboxyethyl)(3,4-dimethoxybenezensulfonyl)amino!-N-hydroxy-acetamide;2-(R)-2-(2-Carbamoylethyl)(4-methoxybenzenesulfonyl)amino!-N-hydroxy-3-methylbutyramide;and 2-(R)-N-Hydroxy-2-((4-methoxybenzensulfonyl)2-(methylcarboxymethylcarbamoyl)ethyl!amino)-3-methylbutyramide.
 10. Apharmaceutical composition for (a) die treatment of a condition selectedfrom to group consisting of arthritis, tissue ulceration, restenosis,periodontal disease, epidermolysis bullosa, scleritis and other diseasescharacterized by matrix metalloproteinase activity, sepsis, septic shockand other diseases involving the production of tumor necrosis factor(TNF) or (b) the inhibition of matrix metalloproteinases or theproduction of tumor necrosis factor (TNF) in a mammal, comprising anamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof, efective in such treatments and a pharmaceutically acceptablecarrier.
 11. A method for the inhibition of (a) matrixmetalloproteinases or (b) the production of tumor necrosis factor (TNF)in a mammal, comprising administering to said mammal an effective amountof a compound of claim 1 or a pharmaceutically acceptable salt thereof.12. A method for treating arthritis, in a mammal, comprisingadministering to said mammal an amount of a compound of claim 1 or apharmaceutically acceptable salt thereof, effective in treating such acondition.
 13. A method of preparing a compound of the formula ##STR10##or the pharmaceutically acceptable salts hereof, wherein n is 1 to 6;Xis hydroxy, (C₁ -C₆)alkoxy or NR¹ R² wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, (C₆ -C₁₀)aryl, (C₆ -C₁₀)aryl(C₁ C₆)alkyl, (C₆ -C₁₀)aryl(C₆-C₁₀)aryl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl,(C₃ -C₆)cycloalkyl(C₁ -C₆)alkyl, R⁵ (C₂ -C₆)alkyl, (C₁-C₅)alkyl(CHR⁵)(C₁ -C₆)alkyl wherein R⁵ is hydroxy, (C₁ -C₆)acyloxy, (C₁-C₆)alkoxy, (C₁ -C₆)acylamino, (C₁ -C₆)alkylthio, (C₆ -C₁₀)arylthio, (C₁-C₆)alkylsulfinyl, (C₆ -C₁₀)arylsulfinyl, (C₁ -C₆)alkylsulfoxyl, (C₆-C₁₀)arylsulfoxyl, amino, (C₁ -C₆)alkylamino, ((C₁ -C₆)alkyl)₂ amino:and CH(R⁷)COR⁸ wherein R⁷ is hydrogen, (C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁-C₆)alkyl, (C₁ -C₆)alkylthio(C₁ -C₆)alkyl, (C₆ -C₁₀)arylthio(C₁-C₆)alkyl, (C₁ -C₆)alkylsulfinyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfinyl(C₁-C₆)alkyl, (C₁ -C₆)alkylsulfonyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfonyl(C₁-C₆)alkyl, hydroxy(C₁ -C₆)alkyl, amino(C₁ -C₆)alkyl, (C₁-C₆)alkylamino(C₁ -C₆)alkyl, ((C₁ -C₆)alkyl₃ amino(C₁ -C₆)alkyl, R⁹ R¹⁰NCO(C₁ -C₆)alkyl or R⁹ OCO(C₁ -C₆)alkyl wherein R⁹ and R¹⁰ are eachindependently selected from the group consisting of hydrogen, (C₁-C₆)alkyl, and (C₆ -C₁₀)aryl(C₁ -C₆)alkyl: and R⁸ is R¹¹ O or R¹¹ R¹² Nwherein R¹¹ and R¹² are each independently selected from the groupconsisting of hydrogen, (C₁ -C₆)alkyl, and (C₆ -C₁₀)aryl(C₁ -C₆)alkyl;R³ and R⁴ are each independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, trifluoromethyl, trifluoromethyl(C₁ -C₆)alkyl,(C₁ -C₆)alkyl (difluoromethylene), (C₁ -C₃)alkyl(difluoromethylene)(C₁-C₃)alkyl, (C₆ -C₁₀)aryl, (C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₆-C₁₀)aryl, (C₆ -C₁₀)aryl(C₆ -C₁₀)aryl(C₁ -C₆)alkyl, (C₃ -C₆)cycloalkyl,(C₃ -C₆)cycloalkyl(C₁ -C₆)alkyl, hydroxy(C₁ -C₆)alkyl, (C₁-C₆)acyloxy(C₁ -C₆)alkyl, (C₁ -C₆)alkoxy(C₁ -C₆)alkyl, (C₁-C₆)acylamino(C₁ -C₆)alkyl, (C₆ -C₁₀)aryl(C₁ -C₆)alkoxy(C₁ -C₆)alkyl,(C₁ -C₆)alkylthio(C₁ -C₆)alkyl, (C₆ -C₁₀)arylthio(C₁ -C₆)alkyl, (C₁-C₆)alkylsulfinyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfinyl(C₁ -C₆)alkyl, (C₁-C₆)alkylsulfonyl(C₁ -C₆)alkyl, (C₆ -C₁₀)arylsulfonyl(C₁ -C₆)alkyl,amino(C₁ -C₆)alkyl, (C₁ -C₆)alkylamino(C₁ -C₆)alkyl, ((C₁-C₆)alkylamino₂ (C₁ -C₆)alkyl, R¹³ CO(C₁ -C₆)alkyl wherein R¹³ is R²⁰ Oor R²⁰ R²¹ N wherein R²⁰ and R²¹ are each independently selected fromthe group consisting of hydrogen, (C₁ -C₆)alkyl, or (C₆ -C₁₀)aryl(C₁-C₆)alkyl; or R³ and R⁴, or R²⁰ and R²¹ may be taken together to form a(C₃ -C₆)cycloalkyl, oxacyclohexyl, or thiocyclohexyl, and Ar is (C₆-C₁₀)aryl, (C₁ -C₆)alkyl(C₆ -C₁₀)aryl, (C₁ -C₆)alkoxy(C₆ -C₁₀)aryl, ((C₁-C₆)alkoxy)₂ (C₆ -C₁₀)aryl, or (C₆ -C₁₀)aryloxy(C₆ -C₁₀)aryl; with theproviso that when either R¹ or R² is CH(R⁷)COR⁸ wherein R⁷ and R⁸ are asdefined above, the other of R¹ or R² is hydrogen, (C₁ -C₆)alkyl, orbenzyl; comprising reacting a compound of the formula ##STR11## whereinn, X, R³, R⁴ and Ar are as defined above with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-hydroxybenztriazole andhydroxylamine.